Systemic lupus erythematosus (SLE or lupus) is a complex, multi-organ, clinically heterogeneous, potentially fatal autoimmune disease with substantial genetic and environmental components. In U.S., SLE affects ~2 million people, mostly women (~90%), and prevalence is >3-5 times higher in individuals of African, Asian and Hispanic ancestries compared to European ancestry. Despite its public health importance, SLE pathogenesis is not well understood. Infection is a leading cause of morbidity and mortality, accounting for >25% of deaths in SLE patients. Reactive oxygen species (ROS), such as superoxide and hydrogen peroxide are key for defense against invading microbial pathogens, and are produced by the multi-protein NADPH- oxidase (NADPHO) system during phagocytosis. This multi-protein complex is encoded by 7 essential genes: NCF1, NCF2, NCF4, CYBA,CYBB, Rac1 or Rac2. Although NADPHO is likely to be important in SLE pathophysiology, thus far, none of the 7 genome-wide association studies detected SLE association. Using large multi-ethnic cohorts (N > 17,000 from European-Americans (EA), African-Americans (AA), Hispanics (HS), and Koreans (KR)), we have identified at least 7 independent and potentially functional SLE-susceptibility variants (10-44<p<10-7) within NCF2. We also have suggestive evidence (10-4<p<10-2) of multiple variants from genes encoding the other subunits of NADPHO, implicating its causal role in SLE susceptibility. We identified both ethnically-robust and ethnicity-specific SLE predisposing variants. Moreover, our data suggest that variation in NADPHO may influence SLE clinical sub-phenotypes; i.e., in EA, missense rs17849502 is more strongly associated with lupus nephritis (odds ratio (OR) = 3.5), and with SLE in males (OR = 4.23), compared to SLE in general (OR = 2.5). Follow up bioinformatic and molecular modeling analyses on selected variants show high conservation across vertebrates, implicating potential functional roles and predicting detrimental effects on NADPHO assembly that ultimately disrupt ROS production. We hypothesize that dense genotyping using individuals from 4 ethnically diverse populations, combined with conditional analysis and molecular modeling, will identify multiple potentially functional variants (rare and common), both ethnically robust and ethnicity-specific, within NADPHO genes. We propose three Specific Aims: (1) Identify and pinpoint SLE- predisposing variants within genes encoding the NADPHO complex, (2) Elucidate genetic variants contributing to the clinical heterogeneity of SLE, (3) Use these in conjunction with molecular modeling to predict mechanistic effects of SLE-predisposing functional variants. With our preliminary findings, research strategies, available biomaterials, resources, infrastructure, and experience, expertise and track records of our research team, we have excellent potential to successfully complete the proposed project. Ultimately, a set of novel functional variants will be made available to the scientific community and provide a basis for future biological experiments to define how NADPHO contributes to the pathological mechanisms of lupus.